Ethers of 7-desmethylrapamycin

ABSTRACT

This invention provides ethers of 7-desmethylrapamycin which are useful in inducing immunosuppression and in the treatment of transplantation rejection, autoimmune diseases, solid tumors, fungal infections, and vascular disease.

[0001] This application claims priority from copending provisionalapplication Serial No. 60/237,469, filed Oct. 2, 2000, the entiredisclosure of which is hereby incorporated by reference.

BACKGROUND OF THE INVENTION

[0002] This invention relates to ethers of 7-desmethylrapamycin, whichare useful in inducing immunosuppression and in the treatment oftransplantation rejection, autoimmune diseases, solid tumors, fungalinfections, and vascular disease or disorders.

[0003] Rapamycin is a macrocyclic triene antibiotic produced byStreptomyces hygroscopicus, which was found to have antifungal activity,particularly against Candida albicans, both in vitro and in vivo [C.Vezina et al., J. Antibiot. 28, 721 (1975); S. N. Sehgal et al., J.Antibiot. 28, 727 (1975); H. A. Baker et al., J. Antibiot. 31, 539(1978); U.S. Pat. Nos. 3,929,992; and 3,993,749]. Additionally,rapamycin alone (U.S. Pat. No. 4,885,171) or in combination withpicibanil (U.S. Pat. No. 4,401,653) has been shown to have antitumoractivity.

[0004] The immunosuppressive effects of rapamycin have been disclosed inFASEB 3, 3411 (1989). Cyclosporin A and FK-506, other macrocyclicmolecules, also have been shown to be effective as immunosuppressiveagents, therefore useful in preventing transplant rejection [FASEB 3,3411 (1989); FASEB 3, 5256 (1989); R. Y. Calne et al., Lancet 1183(1978); and U.S. Pat. No. 5,100,899]. R. Martel et al. [Can. J. Physiol.Pharmacol. 55, 48 (1977)] disclosed that rapamycin is effective in theexperimental allergic encephalomyelitis model, a model for multiplesclerosis; in the adjuvant arthritis model, a model for rheumatoidarthritis; and effectively inhibited the formation of IgE-likeantibodies.

[0005] Rapamycin is also useful in preventing or treating systemic lupuserythematosus [U.S. Pat. No. 5,078,999], pulmonary inflammation [U.S.Pat. No. 5,080,899], insulin dependent diabetes mellitus [U.S. Pat. No.5,321,009], skin disorders, such as psoriasis [U.S. Pat. No. 5,286,730],bowel disorders [U.S. Pat. No. 5,286,731], smooth muscle cellproliferation and intimal thickening following vascular injury [U.S.Pat. Nos. 5,288,711 and 5,516,781], adult T-cell leukemia/lymphoma[European Patent Application 525,960 A1], ocular inflammation [U.S. Pat.No. 5,387,589], malignant carcinomas [U.S. Pat. No. 5,206,018], cardiacinflammatory disease [U.S. Pat. No. 5,496,832], and anemia [U.S. Pat.No. 5,561,138].

[0006] Ethers of rapamycin are disclosed in U.S. Pat. No. 5,665,772. Inparticular, 42-O-(2-hydroxy)ethyl rapamycin, also known as SDZ-RAD, hasbeen reported to be useful in treating or inhibiting transplantrejection.

[0007] The preparation and use of 7-desmethylrapamycin and certainderivatives thereof are disclosed in U.S. Pat. No. 5,728,710.

DESCRIPTION OF THE INVENTION

[0008] This invention provides ethers of 7-desmethylrapamycin having thestructure

[0009] wherein

[0010] R¹ and R² are each, independently, hydrogen, thioalkyl of 1-6carbon atoms, arylalkyl of 7-10 carbon atoms, hydroxyalkyl of 1-6 carbonatoms, dihydroxyalkyl of 1-6 carbon atoms, alkoxyalkyl of 2-12 carbonatoms, hydroxyalkoxyalkyl of 2-12 carbon atoms, acyloxyalkyl of 3-12carbon atoms, aminoalkyl of 1-6 carbon atoms, alkylaminoalkyl of 1-6carbon atoms per alkyl group, dialkylaminoalkyl of 1-6 carbon atoms peralkyl group, alkoxycarbonylaminoalkyl of 3-12 carbon atoms,acylaminoalkyl of 3-12 carbon atoms, alkenyl of 2-7 carbon atoms,arylsulfamidoalkyl having 1-6 carbon atoms in the alkyl group,hydroxyalkylallyl of 4-9 carbon atoms, dihydroxyalkylallyl of 4-9 carbonatoms, or dioxolanylallyl;

[0011] with the proviso that R¹ and R² are both not hydrogen, or apharmaceutically acceptable salt thereof which are useful for inducingimmunosuppression, and in the treatment of transplantation rejection,graft vs. host disease, autoimmune diseases, diseases of inflammation,adult T-cell leukemia/lymphoma, solid tumors, fungal infections,cardiovascular disease, cerebral vascular disease, peripheral vasculardisease or hyperproliferative vascular disorders.

[0012] When applicable, pharmaceutically acceptable salts can be formedfrom organic and inorganic bases (i.e., when a compound contains a freehydroxyl group), such as alkali metal salts (for example, sodium,lithium, or potassium) alkaline earth metal salts, ammonium salts,alkylammonium salts containing 1-6 carbon atoms or dialkylammonium saltscontaining 1-6 carbon atoms in each alkyl group, and trialkylammoniumsalts containing 1-6 carbon atoms in each alkyl group, when therapamycin or antiestrogen contains a suitable acidic moiety.

[0013] The term alkyl includes both branched and straight chainmoieties. It is preferred that aryl groups are phenyl or naphthyl. Thisinvention covers compounds in which the stereochemistry of the7-position is racemic (R, S) as well as the individual R and Sstereoisomers at the 7-position.

[0014] As used in accordance with this invention, the term “providing,”with respect to providing a compound or substance covered by thisinvention, means either directly administering such a compound orsubstance, or administering a prodrug, derivative, or analog which willform the equivalent amount of the compound or substance within the body.

[0015] Of the compounds of this invention, it is preferred that R² ishydrogen, and more prefered that R² is hydrogen and R¹ is hydroxyalkyl.42-O-(2-Hydroxy)ethyl 7-desmethylrapamycin acid is particularlypreferred.

[0016] The reagents used in the preparation of the compounds of thisinvention can be either commercially obtained or can be prepared bystandard procedures described in the literature.

[0017] The preparation of the ethers of rapamycin, from which the7-desmethylrapamycin ethers are made from, are described in U.S. Pat.No. 5,665,772, which is hereby incorporated by reference. The conversionof the 7-(S)-methoxy group of the rapamycin hydroxyester to the7-(R,S)-hydroxy group can be accomplished by nucleophilic substitutionin the mixture of water and aprotic organic solvent such as acetonitrilein acidic condition. The ratio of aqueous to organic solvent ispreferred between 1:9 and 9:1, more preferred is between 1:2 and 2:1.Most preferred ratio of aqueous to organic solvent is 1:1. Resolution ofthe 7-isomers can be accomplished by standard methodology, such aspreparative HPLC.

[0018] The antifungal activity for the ethers of 7-desmethylrapamycin ofthis invention was confirmed in a standard pharmacological testprocedure which measured the ability of the compound being evaluated toinhibit fungal growth. 42-O-(2-Hydroxy)ethyl 7-desmethylrapamycin acid(Compound I) was evaluated as a representative compound of thisinvention. The procedure used and results obtained are briefly describedbelow. A 96 U-bottom microtiter plate was filled (50 μl/well) with RPMI1640. The compounds to be evaluated were placed in appropriate wells,and serial diluted in successive wells to provide 11 dilutions. Theconcentrations ranged from 64 through 0.06 μg/ml. An adjusted inoculumof fungi (50 μl) was added to each well and the plates were incubated at35° C. for 24-48 hours. The MIC is the lowest concentration of compoundwhich completely inhibited growth of organism in the wells. Thefollowing table shows the results obtained in this standardpharmacological test procedure. Where the same fungi is listed more thanonce, it indicates that more than one strain was evaluated. Nystatin andamphotericin B were used for the purpose of comparison. TABLE 1ANTIFUNGAL ACTIVITY (MIC in μg/mL) Com- Ampho- Yeast/Fungi ID pound INystatin tericin β Candida albicans 1063 1 1 ≦0.06 Candidu albicans 11172 1 0.12 Candida albicans ATCC 90028 2 1 0.12 Candida parapsilosis 94 -9 2 1 0.12 Candida parapsilosis 94 - 8 2 2 ≦0.06 Candida parapsilosisATCC 90018 2 2 ≦0.06 Candida pseudotropicalis ATCC 28838 2 1 ≦0.06Candtda tropicalis 94 - 14 0.5 1 ≦0.06 Candida tropicalis 94 - 13 0.5 1≦0.06 Candida krussii 94 - 2 0.5 1 0.12 Candida lusitaniae 94 - 3 1 1≦0.06 Candida rugosa 94 - 10 1 1 0.25 Aspergillus fumigatus ATCC 2693364 2 0.25 Aspergillus niger S430 64 1 0.25 Aspergillus niger S399 64 20.50

[0019] The results obtained in this standard pharmacological testprocedure demonstrate that the compounds of this invention are useful asantifungal agents.

[0020] The antineoplastic activity of the compounds of this inventionwere confirmed in a standard pharmacological test procedure whichmeasures the inhibition of U87MG human glioblastoma cell growth (as afunction of ³H-thymidine incorporation), using 42-O-(2-hydroxy)ethyl7-desmethylrapamycin (Compound I) as a representative compound of thisinvention. The following briefly describes the procedure used andresults obtained. U87MG human glioblastoma cells (ATCC # HTB-14;available from the American Type Culture Collection; 10801 UniversityBoulevard; Manassas, Va. 20110;), were grown in the following media.

[0021] Growth Medium

[0022] BRL Minimum Essential Medium with Earle Salts (500 mL)

[0023] +5 mL BRL MEM Non-Essential Amino Acids (10 mM)

[0024] +5 mL BRL Penicillin-Streptomycin (10000 u/mL, 10000 μg/mL)

[0025] +5 mL BRL Na Pyruvate Solution (100 mM)

[0026] +5 mL BRL L-Glutamine 200 mM

[0027] +50 mL BRL Fetal Bovine Serum (Qualified)

[0028] Test Procedure

[0029] 1. Cells were trypsinized and plated at a concentration of 10⁴cells/well in a final volume of 200 μL growth medium in 96-well flatbottom plates and allowed to adhere for 24 hours at 37° C.

[0030] 2. The media was removed by aspiration with care to not disturbthe cell monolayer. 200 μL of fresh growth media was added per well,allowing enough wells for samples to be run in triplicate. Testcompounds were added in 10 μL phosphate buffer solution (PBS) andincubated for another 48 hours at 37° C.

[0031] 3. During the last 5 hours of incubation, plates were labeledwith 1 μCi ³H thymidine per well. (New England Nuclear thymidine,catalog # NET-027, 6.7 Ci/mmole). The 1μCi was added in 10 μL of PBS (onthe day of harvest). The plates were returned to the incubator for thelast 5 hours.

[0032] 4. The radioactive media was removed by aspiration, with care notto disturb the cell monolayer. Then 50 μL of BRL 10×Trypsin was added toeach well, followed by incubation at 37° C. for 10 minutes or until themonolayer was loosened from the well bottom. Samples were harvested on aglass fiber filter mat using a Skatron 96 well harvester. Mats werecounted in a Wallac Betaplate counter.

[0033] Results Compound IC₅₀ Compound I 3.5 ng/mL

[0034] The results obtained in this standard pharmacological testprocedure show that the compounds of this invention inhibit tumor cellgrowth and are therefore useful as antineoplastic agents. In particular,the compounds of this invention are useful in treating or inhibiting thegrowth of solid tumors, including sarcomas and carcinomas, such asastrocytomas, prostate cancer, breast cancer, small cell lung cancer,and ovarian cancer.

[0035] The compounds of this invention are also useful treatment orinhibition of transplantation rejection such as kidney, heart, liver,lung, bone marrow, pancreas (islet cells), cornea, small bowel, and skinallografts, and heart valve xenografts; in the treatment or inhibitionof graft vs. host disease; in the treatment or inhibition of autoimmunediseases such as lupus, rheumatoid arthritis, diabetes mellitus,myasthenia gravis, and multiple sclerosis; and diseases of inflammationsuch as psoriasis, dermatitis, eczema, seborrhea, inflammatory boweldisease, pulmonary inflammation (including asthma, chronic obstructivepulmonary disease, emphysema, acute respiratory distress syndrome,bronchitis, and the like) and ocular uveitis; adult T-cellleukemia/lymphoma; fungal infections; hyperproliferative vasculardiseases such as restenosis; graft vascular atherosclerosis; andcardiovascular disease, cerebral vascular disease, and peripheralvascular disease, such as coronary artery disease, cerebrovasculardisease, arteriosclerosis, atherosclerosis, nonatheromatousarteriosclerosis, or vascular wall damage from cellular events leadingtoward immune mediated vascular damage, and inhibiting stroke ormultiinfarct dementia.

[0036] When used for restenosis, it is preferred that the compounds ofthis invention are used to treat restenosis that occurs following anangioplasty procedure. When used for this treating restenosis followingan angioplasty, the compounds of this invention can be administeredprior to the procedure, during the procedure, subsequent to theprocedure, or any combination of the above.

[0037] It is contemplated that when the compounds of this invention areused as an immunosuppressive or antiinflammatory agent, they can beadministered in conjunction with one or more other immunoregulatoryagents. Such other immunoregulatory agents include, but are not limitedto azathioprine, corticosteroids, such as prednisone andmethylprednisolone, cyclophosphamide, rapamycin, cyclosporin A, FK-506,OKT-3, mycophenolate, and ATG. By combining the compounds of thisinvention with such other drugs or agents for inducing immunosuppressionor treating inflammatory conditions, the lesser amounts of each of theagents are required to achieve the desired effect. The basis for suchcombination therapy was established by Stepkowski whose results showedthat the use of a combination of rapamycin and cyclosporin A atsubtherapeutic doses significantly prolonged heart allograft survivaltime. [Transplantation Proc. 23: 507 (1991)].

[0038] When used in the treatment or inhibition of vascular disease, itis contemplated that the compounds of this invention may be used as thesole active ingredient to provide the cardiovascular, cerebral, orperipheral vascular benefits covered by this invention, or may beadministered in combination with other agents which provide beneficialcardiovascular, cerebral, or peripheral vascular effects. Such agentsare generally in the classes of compounds known as ACE inhibitors, suchas quinapril, perindopril, ramipril, captoprii, trandolapril,fosinopril, lisinopril, moexipril, and enalapril; angiotensin IIreceptor antagonists, such as candesartan, irbesartan, losartan,valsartan, and telmisartan; fibric acid derivatives, such as clofibrate,and gemfibrozil; HMG Co-A reductase inhibitors, such as cerivastatin,fluvastatin, atorvastatin, lovastatin, pravastatin, simvastatin; betaadrenergic blocking agents, such as sotalol, timolol, esmolol,carteolol, propranolol, betaxolol, penbutolol, nadolol, acebutolol,atenolol, metoprolol, and bisoprolol; calcium channel blockers, such asnifedipine, verapamil, nicardipine, diltiazem, nimodipine, amlodipine,felodipine, nisoldipine, and bepridil; antioxidants; anticoagulants suchas, warfarin, dalteparin, heparin, enoxaparin, and danaparoid; andagents useful in hormone replacement therapy containing estrogens, suchas conjugated estrogens, ethinyl estradiol, 17-beta-estradiol,estradiol, and estropipate.

[0039] When administered for the treatment or inhibition of a particulardisease state or disorder, it is understood that the effective dosage ofthe ether of 7-desmethylrapamycin may vary depending upon the particularcompound utilized, the mode of administration, the condition, andseverity thereof, of the condition being treated, as well as the variousphysical factors related to the individual being treated. As used inaccordance with invention, satisfactory results may be obtained when theether of 7-desmethylrapamycin is administered in a daily oral dosage offrom about projected daily dosages of active compound would be 0.1 μg/kg-100 mg/kg, preferably between 0.001-25 mg/kg, and more preferablybetween 0.01-5 mg/kg. The projected daily dosages are expected to varywith route of administration.

[0040] Such doses may be administered in any manner useful in directingthe active compounds herein to the recipient's bloodstream, includingorally, via implants, parenterally (including intravenous,intraperitoneal and subcutaneous injections), rectally, intranasally,vaginally, and transdermally.

[0041] Oral formulations containing the active compounds of thisinvention may comprise any conventionally used oral forms, includingtablets, capsules, buccal forms, troches, lozenges and oral liquids,suspensions or solutions. Capsules may contain mixtures of the activecompound(s) with inert fillers and/or diluents such as thepharmaceutically acceptable starches (e.g. corn, potato or tapiocastarch), sugars, artificial sweetening agents, powdered celluloses, suchas crystalline and microcrystalline celluloses, flours, gelatins, gums,etc. Useful tablet formulations may be made by conventional compression,wet granulation or dry granulation methods and utilize pharmaceuticallyacceptable diluents, binding agents, lubricants, disintegrants, surfacemodifying agents (including surfactants), suspending or stabilizingagents, including, but not limited to, magnesium stearate, stearic acid,talc, sodium lauryl sulfate, microcrystalline cellulose,carboxymethylcellulose calcium, polyvinylpyrrolidone, gelatin, alginicacid, acacia gum, xanthan gum, sodium citrate, complex silicates,calcium carbonate, glycine, dextrin, sucrose, sorbitol, dicalciumphosphate, calcium sulfate, lactose, kaolin, mannitol, sodium chloride,talc, dry starches and powdered sugar. Preferred surface modifyingagents include nonionic and anionic surface modifying agents.Representative examples of surface modifying agents include, but are notlimited to, poloxamer 188, benzalkonium chloride, calcium stearate,cetostearl alcohol, cetomacrogol emulsifying wax, sorbitan esters,colloidol silicon dioxide, phosphates, sodium dodecylsulfate, magnesiumaluminum silicate, and triethanolamine. Oral formulations herein mayutilize standard delay or time release formulations to alter theabsorption of the active compound(s). The oral formulation may alsoconsist of administering the active ingredient in water or a fruitjuice, containing appropriate solubilizers or emulsifiers as needed.

[0042] In some cases it may be desirable to administer the compoundsdirectly to the airways in the form of an aerosol.

[0043] The compounds of this invention may also be administeredparenterally or intraperitoneally. Solutions or suspensions of theseactive compounds as a free base or pharmacologically acceptable salt canbe prepared in water suitably mixed with a surfactant such ashydroxy-propylcellulose. Dispersions can also be prepared in glycerol,liquid polyethylene glycols and mixtures thereof in oils. Under ordinaryconditions of storage and use, these preparation contain a preservativeto prevent the growth of microorganisms.

[0044] The pharmaceutical forms suitable for injectable use includesterile aqueous solutions or dispersions and sterile powders for theextemporaneous preparation of sterile injectable solutions ordispersions. In all cases, the form must be sterile and must be fluid tothe extent that easy syringability exists. It must be stable under theconditions of manufacture and storage and must be preserved against thecontaminating action of microorganisms such as bacteria and fungi. Thecarrier can be a solvent or dispersion medium containing, for example,water, ethanol, polyol (e.g., glycerol, propylene glycol and liquidpolyethylene glycol), suitable mixtures thereof, and vegetable oils.

[0045] For the purposes of this disclosure, transdermal administrationsare understood to include all administrations across the surface of thebody and the inner linings of bodily passages including epithelial andmucosal tissues. Such administrations may be carried out using thepresent compounds, or pharmaceutically acceptable salts thereof, inlotions, creams, foams, patches, suspensions, solutions, andsuppositories (rectal and vaginal).

[0046] Transdermal administration may be accomplished through the use ofa transdermal patch containing the active compound and a carrier that isinert to the active compound, is non toxic to the skin, and allowsdelivery of the agent for systemic absorption into the blood stream viathe skin. The carrier may take any number of forms such as creams andointments, pastes, gels, and occlusive devices. The creams and ointmentsmay be viscous liquid or semisolid emulsions of either the oil-in-wateror water-in-oil type. Pastes comprised of absorptive powders dispersedin petroleum or hydrophilic petroleum containing the active ingredientmay also be suitable. A variety of occlusive devices may be used torelease the active ingredient into the blood stream such as asemi-permeable membrane covering a reservoir containing the activeingredient with or without a carrier, or a matrix containing the activeingredient. Other occlusive devices are known in the literature.

[0047] Suppository formulations may be made from traditional materials,including cocoa butter, with or without the addition of waxes to alterthe suppository's melting point, and glycerin. Water soluble suppositorybases, such as polyethylene glycols of various molecular weights, mayalso be used.

[0048] The preparation of representative examples of this invention isdescribed below.

EXAMPLE 1 Preparation of 42-O-(2-Hydroxy)ethyl 7-desmethylrapamycin(Compound I)

[0049] 42-O -(2-Hydroxy)ethyl rapamycin (30 mg, 3.13×10⁻⁵ mole) wasdissolved in 20 mL acetonitrile and 20 mL 0.1 N hydrochloric acid. Thesolution was kept at room temperature overnight. Then the reactionmixture was extracted with 80 mL methylene chloride (CH₂Cl₂) in aseparatory funnel. The organic layer was washed 100 mL water, 50 mL 0.1M sodium phosphate buffer (pH 7) and then 100 mL water again. Themethylene chloride was removed by rotary evaporation. The pure compoundI was performed by preparative HPLC on a Prep Nova-pak HR C18 (300×19mm) column from Waters. Compound I eluted at between 11.7-13.1 min and42-O -(2-hydroxy)ethyl rapamycin eluted at 22.7 min using a gradient(0-5 min 40% A, 40% B, 5-25 min from 50% B to 70%, 25-30 min 70% B to100%B). A is 90% water, 10% acetonitrile; B is 10% water, 90%acetonitrile. The fraction was collected and extracted by 2×100 mLmethylene chloride. The organic layer was combined and dried withanhydrous sodium sulfate. Then most of the solvent was removed by rotaryevaporation and final product was precipitated by hexane. Compound I, awhite solid was obtained. Positive ion mass spectrum shows the molecularion specie [M+NH₄]⁺ at m/z 961.6. The loss of 14 from the mass of42-O-(2-hydroxy)ethyl rapamycin indicates the conversion of a methoxy toa hydroxy. ¹H NMR (400 MHz) of compound I in CDCl₃ shows the loss of7-position CH₃O-resonance at 3.14 ppm comparing to the ¹H NMR of42-O-(2-hydroxy)ethyl rapamycin.

What is claimed is:
 1. A compound having the structure

wherein R¹ and R² are each, independently, hydrogen, thioalkyl of 1-6carbon atoms, arylalkyl of 7-10 carbon atoms, hydroxyalkyl of 1-6 carbonatoms, dihydroxyalkyl of 1-6 carbon atoms, alkoxyalkyl of 2-12 carbonatoms, hydroxyalkoxyalkyl of 2-12 carbon atoms, acyloxyalkyl of 3-12carbon atoms, aminoalkyl of 1-6 carbon atoms, alkylaminoalkyl of 1-6carbon atoms per alkyl group, dialkylaminoalkyl of 1-6 carbon atoms peralkyl group, alkoxycarbonylaminoalkyl of 3-12 carbon atoms,acylaminoalkyl of 3-12 carbon atoms, alkenyl of 2-7 carbon atoms,arylsulfamidoalkyl having 1-6 carbon atoms in the alkyl group,hydroxyalkylallyl of 4-9 carbon atoms, dihydroxyalkylallyl of 4-9 carbonatoms, or dioxolanylallyl; with the proviso that R¹ and R² are both nothydrogen, or a pharmaceutically acceptable salt thereof.
 2. The compoundaccording to claim 1, wherein R² is hydrogen.
 3. The compound accordingto claim 2, wherein R¹ is hydroxyalkyl of 1-6 carbon atoms.
 4. Thecompound of claim 1, which is 42-O-(2-hydroxy)ethyl 7-desmethylrapamycinacid is particularly preferred..
 5. A method of treating or inhibitingtransplant rejection or graft vs. host disease in a mammal in needthereof, which comprises providing to said mammal an effective amount ofa compound having the structure

wherein R¹ and R² are each, independently, hydrogen, thioalkyl of 1-6carbon atoms, arylalkyl of 7-10 carbon atoms, hydroxyalkyl of 1-6 carbonatoms, dihydroxyalkyl of 1-6 carbon atoms, alkoxyalkyl of 2-12 carbonatoms, hydroxyalkoxyalkyl of 2-12 carbon atoms, acyloxyalkyl of 3-12carbon atoms, aminoalkyl of 1-6 carbon atoms, alkylaminoalkyl of 1-6carbon atoms per alkyl group, dialkylaminoalkyl of 1-6 carbon atoms peralkyl group, alkoxycarbonylaminoalkyl of 3-12 carbon atoms,acylaminoalkyl of 3-12 carbon atoms, alkenyl of 2-7 carbon atoms,arylsulfamidoalkyl having 1-6 carbon atoms in the alkyl group,hydroxyalkylallyl of 4-9 carbon atoms, dihydroxyalkylallyl of 4-9 carbonatoms, or dioxolanylallyl; with the proviso that R¹ and R² are both nothydrogen, or a pharmaceutically acceptable salt thereof.
 6. A method oftreating or inhibiting a solid tumor in a mammal in need thereof, whichcomprises providing to said mammal a compound having the structure

wherein R¹ and R² are each, independently, hydrogen, thioalkyl of 1-6carbon atoms, arylalkyl of 7-10 carbon atoms, hydroxyalkyl of 1-6 carbonatoms, dihydroxyalkyl of 1-6 carbon atoms, alkoxyalkyl of 2-12 carbonatoms, hydroxyalkoxyalkyl of 2-12 carbon atoms, acyloxyalkyl of 3-12carbon atoms, aminoalkyl of 1-6 carbon atoms, alkylaminoalkyl of 1-6carbon atoms per alkyl group, dialkylaminoalkyl of 1-6 carbon atoms peralkyl group, alkoxycarbonylaminoalkyl of 3-12 carbon atoms,acylaminoalkyl of 3-12 carbon atoms, alkenyl of 2-7 carbon atoms,arylsulfamidoalkyl having 1-6 carbon atoms in the alkyl group,hydroxyalkylallyl of 4-9 carbon atoms, dihydroxyalkylallyl of 4-9 carbonatoms, or dioxolanylallyl; with the proviso that R¹ and R² are both nothydrogen, or a pharmaceutically acceptable salt thereof.
 7. A method oftreating or inhibiting a fungal infection in a mammal in need thereof,which comprises providing to said mammal an effective amount of acompound having the structure

wherein R¹ and R² are each, independently, hydrogen, thioalkyl of 1-6carbon atoms, arylalkyl of 7-10 carbon atoms, hydroxyalkyl of 1-6 carbonatoms, dihydroxyalkyl of 1-6 carbon atoms, alkoxyalkyl of 2-12 carbonatoms, hydroxyalkoxyalkyl of 2-12 carbon atoms, acyloxyalkyl of 3-12carbon atoms, aminoalkyl of 1-6 carbon atoms, alkylaminoalkyl of 1-6carbon atoms per alkyl group, dialkylaminoalkyl of 1-6 carbon atoms peralkyl group, alkoxycarbonylaminoalkyl of 3-12 carbon atoms,acylaminoalkyl of 3-12 carbon atoms, alkenyl of 2-7 carbon atoms,arylsulfamidoalkyl having 1-6 carbon atoms in the alkyl group,hydroxyalkylallyl of 4-9 carbon atoms, dihydroxyalkylallyl of 4-9 carbonatoms, or dioxolanylallyl; with the proviso that R¹ and R² are both nothydrogen, or a pharmaceutically acceptable salt thereof.
 8. A method oftreating or inhibiting rheumatoid arthritis in a mammal in need thereof,which comprises providing to said mammal an effective amount of acompound having the structure

wherein R¹ and R² are each, independently, hydrogen, thioalkyl of 1-6carbon atoms, arylalkyl of 7-10 carbon atoms, hydroxyalkyl of 1-6 carbonatoms, dihydroxyalkyl of 1-6 carbon atoms, alkoxyalkyl of 2-12 carbonatoms, hydroxyalkoxyalkyl of 2-12 carbon atoms, acyloxyalkyl of 3-12carbon atoms, aminoalkyl of 1-6 carbon atoms, alkylaminoalkyl of 1-6carbon atoms per alkyl group, dialkylaminoalkyl of 1-6 carbon atoms peralkyl group, alkoxycarbonylaminoalkyl of 3-12 carbon atoms,acylaminoalkyl of 3-12 carbon atoms, alkenyl of 2-7 carbon atoms,arylsulfamidoalkyl having 1-6 carbon atoms in the alkyl group,hydroxyalkylallyl of 4-9 carbon atoms, dihydroxyalkylallyl of 4-9 carbonatoms, or dioxolanylallyl; with the proviso that R¹ and R² are both nothydrogen, or a pharmaceutically acceptable salt thereof.
 9. A method oftreating or inhibiting multiple sclerosis in a mammal in need thereof,which comprises providing to said mammal an effective amount of acompound having the structure

wherein R¹ and R² are each, independently, hydrogen, thioalkyl of 1-6carbon atoms, arylalkyl of 7-10 carbon atoms, hydroxyalkyl of 1-6 carbonatoms, dihydroxyalkyl of 1-6 carbon atoms, alkoxyalkyl of 2-12 carbonatoms, hydroxyalkoxyalkyl of 2-12 carbon atoms, acyloxyalkyl of 3-12carbon atoms, aminoalkyl of 1-6 carbon atoms, alkylaminoalkyl of 1-6carbon atoms per alkyl group, dialkylaminoalkyl of 1-6 carbon atoms peralkyl group, alkoxycarbonylaminoalkyl of 3-12 carbon atoms,acylaminoalkyl of 3-12 carbon atoms, alkenyl of 2-7 carbon atoms,arylsulfamidoalkyl having 1-6 carbon atoms in the alkyl group,hydroxyalkylallyl of 4-9 carbon atoms, dihydroxyalkylallyl of 4-9 carbonatoms, or dioxolanylallyl; with the proviso that R¹ and R² are both nothydrogen, or a pharmaceutically acceptable salt thereof.
 10. A method oftreating or inhibiting restenosis in a mammal in need thereof, whichcomprises providing to said mammal an effective amount of a compoundhaving the structure

wherein R¹ and R² are each, independently, hydrogen, thioalkyl of 1-6carbon atoms, arylalkyl of 7-10 carbon atoms, hydroxyalkyl of 1-6 carbonatoms, dihydroxyalkyl of 1-6 carbon atoms, alkoxyalkyl of 2-12 carbonatoms, hydroxyalkoxyalkyl of 2-12 carbon atoms, acyloxyalkyl of 3-12carbon atoms, aminoalkyl of 1-6 carbon atoms, alkylaminoalkyl of 1-6carbon atoms per alkyl group, dialkylaminoalkyl of 1-6 carbon atoms peralkyl group, alkoxycarbonylaminoalkyl of 3-12 carbon atoms,acylaminoalkyl of 3-12 carbon atoms, alkenyl of 2-7 carbon atoms,arylsulfamidoalkyl having 1-6 carbon atoms in the alkyl group,hydroxyalkylallyl of 4-9 carbon atoms, dihydroxyalkylallyl of 4-9 carbonatoms, or dioxolanylallyl; with the proviso that R¹ and R² are both nothydrogen, or a pharmaceutically acceptable salt thereof.
 11. A method oftreating or inhibiting pulmonary inflammation in a mammal in needthereof, which comprises providing to said mammal an effective amount ofa compound having the structure

wherein R¹ and R² are each, independently, hydrogen, thioalkyl of 1-6carbon atoms, arylalkyl of 7-10 carbon atoms, hydroxyalkyl of 1-6 carbonatoms, dihydroxyalkyl of 1-6 carbon atoms, alkoxyalkyl of 2-12 carbonatoms, hydroxyalkoxyalkyl of 2-12 carbon atoms, acyloxyalkyl of 3-12carbon atoms, aminoalkyl of 1-6 carbon atoms, alkylaminoalkyl of 1-6carbon atoms per alkyl group, dialkylaminoalkyl of 1-6 carbon atoms peralkyl group, alkoxycarbonylaminoalkyl of 3-12 carbon atoms,acylaminoalkyl of 3-12 carbon atoms, alkenyl of 2-7 carbon atoms,arylsulfamidoalkyl having 1-6 carbon atoms in the alkyl group,hydroxyalkylallyl of 4-9 carbon atoms, dihydroxyalkylallyl of 4-9 carbonatoms, or dioxolanylallyl; with the proviso that R¹ and R² are both nothydrogen, or a pharmaceutically acceptable salt thereof.
 12. Apharmaceutical composition which comprises a compound having thestructure

wherein R¹ and R² are each, independently, hydrogen, thioalkyl of 1-6carbon atoms, arylalkyl of 7-10 carbon atoms, hydroxyalkyl of 1-6 carbonatoms, dihydroxyalkyl of 1-6 carbon atoms, alkoxyalkyl of 2-12 carbonatoms, hydroxyalkoxyalkyl of 2-12 carbon atoms, acyloxyalkyl of 3-12carbon atoms, aminoalkyl of 1-6 carbon atoms, alkylaminoalkyl of 1-6carbon atoms per alkyl group, dialkylaminoalkyl of 1-6 carbon atoms peralkyl group, alkoxycarbonylaminoalkyl of 3-12 carbon atoms,acylaminoalkyl of 3-12 carbon atoms, alkenyl of 2-7 carbon atoms,arylsulfamidoalkyl having 1-6 carbon atoms in the alkyl group,hydroxyalkylallyl of 4-9 carbon atoms, dihydroxyalkylallyl of 4-9 carbonatoms, or dioxolanylallyl; with the proviso that R¹ and R² are both nothydrogen, or a pharmaceutically acceptable salt thereof, and apharmaceutical carrier.